There is increasing evidence that experimental atherosclerosis begins with injury to the endothelium and terminates in the proliferation of smooth-muscle cells. Polyunsaturated fatty acids may contribute at several points to the progression of an experimental lesion. These fatty acids function in lipid storage, cellular structure and the regulatory control of processes such as cell proliferation. Biological control involves the microsomal biosynthesis of specific fatty acids and the availability of these fatty acids for microsomal oxidation reactions. Biosynthesis is modulated by enzymes, particularly the delta 6-desaturase. Availability is modulated both by metabolic pathways which shunt fatty acids into storage lipids (cholesteryl esters) and structural lipids (phospholipids) and by hydrolase (phospholipase A2 and acid hydrolases) which liberate fatty acids from these lipids. Two microsomal oxidation pathways exist. Lipoxygenase converts fatty acids to hydroperoxy fatty acid derivatives. Cyclooxygenase converts fatty acids to endoperoxides which are then metabolized to prostaglandins, thromboxanes and prostacyclin. These oxidation systems interact with each other and are controlled in part by inhibitors and natural antioxidants such as vitamin E. Substrate and inhibitor specificities are consistent with regulatory control through oxidant stress. We propose that oxidant stress may facilitate sulfhydryl-disulfide interconversions and regulate both cyclase and cyclic phosphodiesterase enzyme systems. Oxidant stress may damage the endothelium and yet oxidant stress may control smooth muscle cell proliferation. Thus experimental atherosclerosis is a complex process modulated in part by polyunsaturated fatty acid metabolism and the subsequent effects, both positive and negative, of oxidant stress. It may be possible to design intervention strategies involving unique fatty acids and/or antioxidants when this process is defined.